The mouse mutant Motor neuron degeneration (Mnd) exhibits an adult-onset progressive degeneration of upper and lower motor neurons, leading to paralysis and premature death. It shows many features with human motor neuron diseases, esp ALS. Studies to identify the primary target of the Mnd mutation will first examine DNA fragments and spinal cord mRNA sizes and levels from candidate genes which are known to map in close proximity to the chromosomal location of Mnd. Analysis of larger pieces of DNA from that region, identified using linked genes, will be studied if necessary. The age of onset and speed of progression of the symptoms are controlled by an additional unlinked gene or genes. DNA from genetics cross of Mnd/Mnd to wild-type AKR/J will be typed using retroviral probes to establish an initial linkage, with confirmation by analysis of specific linked polymorphisms, in order to map this important trait. Further studies of the mechanism of action of the timing effect will combine the genetic information with comparisons of the disease in strains with different time-courses. Such comparisons will include expression of genes which are functionally very close to the primary effects of the mutation, as well as expression of those genes which may be part of the cascade of events which leads to the gradual neuronal degeneration observed. Studies of the Mnd gene plus its timing modifier should be applicable to both spontaneous and hereditary human motor neuron disease. in the former the possibility of enhanced susceptibility to a pathogen or toxin, and/or multigenic effect seem likely in the majority of cases. Other investigators are using the mouse locus information to test human families with unknown map locations, and (as part of this proposal) spinal cord mRNA from human ALS cases will be tested for levels of some of those markers which seem to change most specifically in the mouse disease. Long-range studies to determine the nature of the process which can slow the progression of the symptoms should be especially valuable clinically.